β-amyloid oligomers and cellular prion protein in Alzheimer’s disease

Abstract

Prefibrillar oligomers of the β-amyloid peptide (Aβ) are recognized as potential mediators of Alzheimer's disease (AD) pathophysiology. Deficits in synaptic function, neurotoxicity, and the progression of AD have all been linked to the oligomeric Aβ assemblies rather than to Aβ monomers or to amyloid plaques. However, the molecular sites of Aβ oligomer action have remained largely unknown. Recently, the cellular prion protein (PrP C ) has been shown to act as a functional receptor for Aβ oligomers in brain slices. Because PrP C serves as the substrate for Creutzfeldt-Jakob Disease (CJD), these data suggest mechanistic similarities between the two neurodegenerative diseases. Here, we review the importance of Aβ oligomers in AD, commonalities between AD and CJD, and the newly emergent role of PrP C as a receptor for Aβ oligomers.

Amyloid-β42 Interacts Mainly with Insoluble Prion Protein in the Alzheimer Brain

“…Our assumption is supported by the recent study of Wisniewski and co-workers (30) who observed that the antibody-based interruption of the binding of PrP to A␤42 by intraperitoneal injection of the 6D11 antibody improved behavior and memory in an AD animal model, which is consistent with our own preliminary data. 3 These last two studies agree with the observation by Laurén and co-workers (9) that the binding site of A␤42 is the 6D11 antibody epitope (murine PrP 93-109). Conceivably, interference of A␤42 binding to PrP may represent not only a more appropriate method to assess the role of PrP in the pathogenesis of AD, but also a therapeutic strategy for AD.…”

“…The remarkable hypothesis that PrP C may act as a receptor for A␤42 and play a critical role in the pathogenesis of AD has triggered great interest in the fields of Alzheimer and prion diseases while raising high hopes for finding a cure for AD (3,9). The evidence supporting this new hypothesis is based on two fundamental observations: the direct binding of A␤42 to PrP and the potential pathophysiological role of PrP in A␤42 neurotoxicity in different AD models.…”

“…These are unique neurodegenerative disorders with an infectious, sporadic or genetic etiology, and which are characterized by deposition of misfolded, pathological PrP (PrP Sc ) in the brain (2). Interestingly, a recent interpretation of early and newer observations suggests that PrP C may play a role in the pathogenesis of AD (3). Epidemiological studies suggest that the Met/Val polymorphism at residue 129 in PrP modulates the number of A␤ deposits (4).…”

“…In a genetic AD model where the A␤ plaque burden resulted from APP and presenilin 1 (APPswe/PS1 ⌬E9 ) transgenes, the elimination of PrP (Prnp Ϫ/Ϫ ) rescued the impairment of spatial learning and memory (10). This evidence led the authors to conclude that PrP mediates A␤ neurotoxicity through direct binding to toxic A␤ species (3).…”

Prion Protein and Amyloid Beta Peptide Interact in the Yeast Saccharomyces Cerevisiae

“…Интересной особенностью белка prp и пептида aβ является их спо-собность к взаимодействию: белок prp в мономерной изоформе спе-цифично связывает олигомеры пептида амилоид-бета, то есть является его рецептором, и, таким образом, способен влиять на проявление бо-лезни (Gunther and Strittmatter, 2009). Недавние исследования также показали, что процессы, связанные с неправильной укладкой одного из этих белков, являются серьезным фактором риска для индукции агрега-ции другого (Morales et al, 2010).…”